The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We will measure forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study will be repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside will also be evaluated. Additional secondary studies will evaluate the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibit nitric oxide-mediated blood flow; markers of inflammation and oxidation; and gene expression by microarray and pilot studies of proteomics in sickle cell patients. As of 28 October 2003, we have obtained IRB approval to begin these studies, and we now await FDA approval of an IND for the standard drugs infused in study subjects to assess nitric oxide-dependent blood flow. We anticipate beginning enrollment in mid-December 2003. We plan to evaluate up to 25 subjects, with an interim analysis at 15 patients. These physiological translational studies will determine whether additional studies of statins should be performed to evaluate the efficacy of statins to reduce the clinical severity of sickle cell disease.